1. Field of the Invention
The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof inhibiting 11β-HSD1 enzyme activity, a preparation method of the same, and a pharmaceutical composition comprising the same as an active ingredient.
2. Description of the Related Art
Metabolic syndrome is the disease in increase particularly in advanced countries, in Asia, and in developing countries. This disease is characterized by obesity, type II diabetes, hyperlipidemia, hypertension, arteriosclerosis, coronary heart disease, and chronic renal failure (C. T. Montague et al. (2000), Diabetes, 49, 883-888).
Glucocorticoid (cortisol in human, and corticosterone in rat and mouse) binding to glucocorticoid receptor is a steroid hormone found in almost every vertebrate (Dallman M F, Strack A M, Akana S F et al. 1993; Front Neuroendocrinol 14, 303-347).
This hormone regulates the expressions of liver enzymes involved in gluconeogenesis so as to release glycerol from adipocytes and amino acid from muscle, resulting in the increase of substrate supplement. It has also been reported that glucocorticoid plays an important role in the differentiation of adipocyte precursors into mature adipocytes that can store triglyceride (Bujalska I J et al. 1999; Endocrinology 140, 3188-3196). This implies that the glucocorticoid induced by “stress” is deeply involved in the disease caused by abdominal obesity which is a major risk factor causing type II diabetes, hypertension, and coronary artery disease (Bjorntorp P & Rosmond R 2000; Int. J. Obesity 24, S80-S85).
It was experimentally confirmed that the activity of glucocorticoid could be controlled in tissue level not only by the secretion of cortisol but also by the intracellular interconversion between active cortisol and inactive cortisol mediated by 11β-HSD1 (11β-Hydroxysteroid dehydrogenase type 1) and 11β-HSD2 (11β-Hydroxysteroid dehydrogenase type 2) (Sandeep T C & Walker B R 2001 Trends in Endocrinol & Metab. 12, 446-453).
Glucocorticoid and 11β-HSD1 are known as important factors for the differentiation of adipocytes. The 11β-HSD1 mRNA level is increased in the visceral fat tissue of an obesity patient, compared with that in the subcutaneous tissue. The over-expression of 11β-HSD1 in the fat tissue of a transgenic mouse is related to the up-regulation of corticosterone in the fat tissue, visceral obesity, insulin sensitivity, type II diabetes, hyperlipidemia, and hyperphagia (H. Masuzaki et al (2001), Science, 294, 2166-2170). Thus, it can be said that 11β-HSD1 is mainly involved in visceral obesity and metabolic syndrome.
At this time, 11β-HSD1 converts the inactive glucocorticoid to the active form, suggesting that it plays an important role in activating glucocorticoid receptor in target tissues and in regulating the concentrations of glucocorticoid in there.
It has been confirmed that the above mechanism can be favorably used for the treatment of diabetes and obesity. Particularly, the treatment effect was confirmed when the antiulcerative agent carbenoxolone that can inhibit both 11β-HSD1 and 11β-HSD2 was used for the treatment. This treatment increased insulin sensitivity, and the suppressed 11β-HSD1 reduced intracellular cortisol level, suggesting that the insulin effect could be controlled (Walker B R et al. 1995; J. Clin. Endocrinol. Metab. 80, 3155-3159). The inhibition of 11β-HSD1 in the 11β-HSD1 knock-out mouse weakened the activity of gluconeogenesis enzyme to induce glucocorticoid and reduced the level of plasma glucose responding stress or obesity (Kotelevtsev Y. et al., Proc Natl Acad Sci USA. 1997 Dec. 23; 94 (26):14924-14929), indicating that the inhibition of 11β-HSD1 was effective in lowering plasma glucose and hepatic glucose in type II diabetes. The inhibition of 11β-HSD1 not only reduces the typical diabetes related symptoms but also does not carry any significant side effect.
In the course of study using the non-specific inhibitor carbenoxolone however, a side effect such as blood pressure increase was observed when 11β-HSD2 was inhibited. So, it is necessary to develop an inhibitor that has selectivity to 11β-HSD1.
Osteological development and bone function are also regulated by glucocorticoid. 11β-HSD1 exists in human osteoclasts and osteoblasts. When a healthy volunteer was treated with carbenoxolone, the bone formation marker showed no changes but the bone resorption marker was reduced (Cooper M S et al 2000; Bone 27, 375-381). The inhibition of 11β-HSD1 activity in bone can be used as a protective mechanism in the treatment of osteoporosis.
Further, glucocorticoid is also involved in eye disease like glaucoma. 11β-HSD1 has been known to affect the intraocular pressure in human, and thus the inhibition of 11β-HSD1 is expected to alleviate the increased intraocular pressure in relation to glaucoma (Rauz S et al. 2001; Investigative Ophthalmology & Visual Science 42, 2037-2042).
In the course of study to prepare compounds that can selectively inhibit 11β-HSD1, the present inventors succeeded in synthesizing novel compounds which showed excellent activity to inhibit 11β-HSD1 and to have plasma glucose lowering effect dose-dependently, which were confirmed by in vivo animal study. The present inventors completed this invention by confirming that the novel compounds synthesized by the inventors could be effectively used in the treatment of the following diseases or conditions; non-insulin dependent type II diabetes, insulin resistance, obesity, lipid disorder, metabolic syndrome, and other diseases mediated by the excessive activity of glucocorticoid.